(i) Field of the Invention
The present invention relates to prodrug delivery systems for tertiary amine-containing drugs.
(ii) Background of the Invention
Drug delivery systems are often critical for the safe, effective administration of a biologically active agent. Perhaps the importance of these systems is best realized when patient compliance and consistent dosing are taken under consideration. For instance, reducing the dosing requirement for a drug from four-times-a-day to a single dose per day would have significant value in terms of ensuring patient compliance and optimization of therapy.
Optimization of a drug's bioavailability has many potential benefits. For patient convenience and enhanced compliance it is generally recognized that less frequent dosing is desirable. By extending the period through which the drug is released, a longer duration of action per dose is expected. This will then lead to an overall improvement of dosing parameters such as taking a drug once a day where it has previously required four times a day dosing or once a week or even less frequently when daily dosing was previously required. Many drugs are presently given at a once-a-day dosing frequency. Yet, not all of these drugs have pharmacokinetic properties that are suitable for dosing intervals of exactly twenty-four hours. Extending the period through which these drugs are released would also be beneficial.
One of the fundamental considerations in drug therapy involves the relationship between blood levels and therapeutic activity. For most drugs, it is of primary importance that serum levels remain between a minimally effective concentration and a potentially toxic level. In pharmacokinetic terms, the peaks and troughs of a drug's blood levels ideally fit well within the therapeutic window of serum concentrations. For certain therapeutic agents, this window is sufficiently narrow that dosage formulation becomes critical.
In an attempt to address the need for improved bioavailability profiles, several drug release modulation technologies have been developed. Enteric coatings have been used as a protector of pharmaceuticals in the stomach and microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
A wide range of pharmaceutical formulations provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
While microencapsulation and enteric coating technologies impart enhanced stability and time-release properties to active agent substances these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, degradation of the matrix, or both which is highly dependent the chemical properties and on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with limited active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release of the active agent and, due to the variability of pH and residence times, it is difficult to control the rate of release.
Several implantable drug delivery systems have utilized polypeptide attachment to drugs. Additionally, other large polymeric carriers incorporating drugs into their matrices are used as implants for the gradual release of drug. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films.
However there is still a need for an active agent delivery system that is able to deliver certain active agents which have been heretofore not formulated or difficult to formulate in a sustained release formulation for release over a sustained period of time and which is convenient for patient dosing.
It is known that tertiary amines are an extremely important in various classes of compounds from drug discovery. Many of these drugs are useful in therapeutic areas such as for their effects on the central nervous system (CNS) of a patient that would benefit from sustained release formulations. Tertiary amine-containing drugs have been derivatized to form compounds that enhance solubility of the parent tertiary amine-containing drug and improve targeting of the drug in the body and ultimately release the parent drug in its original form for pharmacological action. These compounds derivatized from tertiary amine containing parent drugs are referred to in the prior art as “delivery systems”, “transient delivery systems”, “prodrugs”, or promoieties and comprise quaternary ammonium salts of parent drug compounds that are labile to enzymatic and/or chemical cleavage in vivo.
However, the derivatives, promoieties and prodrugs of parent tertiary amine-containing drugs of the prior art are concerned with increasing solubility of these drugs, protecting labile moieties on the parent drugs and achieving rapid release of the parent drug from the prodrug moiety with minimal toxicity. Thus far there have been no prodrugs of tertiary amine containing drugs that provide sustained release or zero order kinetics by, for example, decreasing the solubility of the parent drug. There is a generally recognized need for sustained delivery of tertiary amine-containing drugs that reduces the daily dosing requirement and allows for controlled and sustained release of the parent tertiary amine-containing drug and also avoids irregularities of release and cumbersome formulations encountered with typical dissolution controlled sustained release methods.